Identifying Cancers Impacted by CDK8/19.

CDK8 and CDK19 Mediator kinases are transcriptional co-regulators implicated in several types of cancer. Small-molecule CDK8/19 inhibitors have recently entered or are entering clinical trials, starting with breast cancer and acute myeloid leukemia (AML). To identify other cancers where these novel drugs may provide benefit, we queried genomic and transcriptomic databases for potential impact of CDK8, CDK19, or their binding partner CCNC. sgRNA analysis of a panel of tumor cell lines showed that most tumor types represented in the panel, except for some central nervous system tumors, were not dependent on these genes. In contrast, analysis of clinical samples for alterations in these genes revealed a high frequency of gene amplification in two highly aggressive subtypes of prostate cancer and in some cancers of the GI tract, breast, bladder, and sarcomas. Analysis of survival correlations identified a group of cancers where CDK8 expression correlated with shorter survival (notably breast, prostate, cervical cancers, and esophageal adenocarcinoma). In some cancers (AML, melanoma, ovarian, and others), such correlations were limited to samples with a below-median tumor mutation burden. These results suggest that Mediator kinases are especially important in cancers that are driven primarily by transcriptional rather than mutational changes and warrant an investigation of their role in additional cancer types.

Discovery of CDK8/CycC Ligands with a New Virtual Screening Tool.

Selective inhibition of cyclin-dependent kinase 8 and cyclin C (CDK8/CycC) has been suggested as a promising strategy for decreasing mitogenic signals in cancer cells with reduced toxicity toward normal cells. We developed a novel virtual screening protocol for drug development and applied it to the discovery of new CDK8/CycC type II ligands, which is likely to achieve long residence time and specificity. We first analyzed the binding thermodynamics of 11 published pyrazolourea ligands using molecular dynamics simulations and a free-energy calculation method, VM2, and extracted the key binding information to assist virtual screening. The urea moiety was found to be the critical structural contributor of the reference ligands. Starting with the urea moiety, we conducted substructure-based searches with our newly developed superposition and single-point energy evaluation method, followed by free-energy calculations, and singled out three purchasable compounds for bioassay testing. The ranking from the experimental results is completely consistent with the predicted rankings. A potent drug-like compound was found to have a Kd value of 42.5 nm, which is similar to those of the most potent reference ligands; this provided a good starting point for further improvement. This study shows that our novel virtual screening protocol is an accurate and efficient tool for drug development.

Identification of novel selective antagonists for cyclin C by homology modeling and virtual screening.

Cancer is a global multidrug resistant calamity, demanding an urgent need to design a novel/potent anti cancer agent. CDK8, 3/cyclin C biosynthetic pathway plays a specific role in G(0)/G(1)/S phases of cell cycle. Cyclin C is identified as a potential anti cancer target candidate. In order to understand the mechanism of ligand binding and interaction between ligand and cyclin C, a 3D homology model for cyclin C is generated. The cyclin C binding groove can be checked by small ligand molecules leading to inhibition. Virtual screening of molecules from an online data base of ChemBank library throws light to arrive at possible inhibitors for cyclin C inhibition. The molecules with better docking scores and acceptable ADME properties were prioritised to obtain potential lead molecules as cyclin C inhibitors.